Changes in the cohort composition of turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: a nationwide cohort study

Agnethe Berglund, Mette Hansen Viuff, Anne Skakkebæk, Simon Chang, Kirstine Stochholm, Claus Højbjerg Gravholt, Agnethe Berglund, Mette Hansen Viuff, Anne Skakkebæk, Simon Chang, Kirstine Stochholm, Claus Højbjerg Gravholt

Abstract

Background: Knowledge on the prevalence of sex chromosome abnormalities (SCAs) is limited, and delayed diagnosis or non-diagnosis of SCAs are a continuous concern. We aimed to investigate change over time in incidence, prevalence and age at diagnosis among Turner syndrome (TS), Klinefelter syndrome (KS), Triple X syndrome (Triple X) and Double Y syndrome (Double Y).

Methods: This study is a nationwide cohort study in a public health care system. The Danish Cytogenetic Central Registry (DCCR) holds information on all karyotypes performed in Denmark since 1961. We identified all individuals in the DCCR with a relevant SCA during 1961-2014; TS: n = 1156; KS: n = 1235; Triple X: n = 197; and Double Y: n = 287. From Statistics Denmark, which holds an extensive collection of data on the Danish population, complete data concerning dates of death and migrations in and out of Denmark were retrieved for all individuals.

Results: The prevalence among newborns was as follows: TS: 59 per 100,000 females; KS: 57 per 100,000 males; Triple X: 11 per 100,000 females; and Double Y: 18 per 100,000 males. Compared with the expected number among newborns, all TS, 38% of KS, 13% of Triple X, and 18% of Double Y did eventually receive a diagnosis. The incidence of TS with other karyotypes than 45,X (P < 0.0001), KS (P = 0.02), and Double Y (P = 0.03) increased during the study period whereas the incidence of 45,X TS decreased (P = 0.0006). The incidence of Triple X was stable (P = 0.22).

Conclusions: The prevalence of TS is higher than previously identified, and the karyotypic composition of the TS population is changing. Non-diagnosis is extensive among KS, Triple X and Double Y, whereas all TS seem to become diagnosed. The diagnostic activity has increased among TS with other karyotypes than 45,X as well as among KS and Double Y.

Keywords: Age at diagnosis; Double Y syndrome; Incidence; Klinefelter syndrome; Prevalence; Triple X syndrome; Turner syndrome.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the Danish Data Protection Agency (journal number: 2013-41-2017). According to Danish law no approval was obtained by the National Committee on Health Research Ethics since the study solely includes registry data.

Consent for publication

The manuscript contains no individual person’s data in any form.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Absolute prevalence of Turner syndrome, Klinefelter syndrome, Triple X syndrome and Double Y syndrome in the Danish population. The observed number of a Turner syndrome (TS) and Triple X syndrome and b Klinefelter syndrome (KS) and Double Y syndrome (Double Y) being alive during 1970–2014 are illustrated by solid and dotted lines. Deceased or emigrated individuals were subtracted. Dashed lines indicate the expected number assuming a true prevalence of 1) 50 TS per 100,000 at birth; 2) 84 Triple X per 100,000 at birth; 3) 152 KS per 100,000 at birth; and 4) 98 Double Y per 100,000 at birth as well as a similar mortality as in the general population
Fig. 2
Fig. 2
Incidence of Turner syndrome according to karyotype. Incidence of a all Turner syndrome (TS); b 45,X TS; and c TS with other karyotypes per million females during 1970–2014. Solid lines illustrate time trend in incidence during the 1970–2014. P-values indicate the significance level of time trend in incidence
Fig. 3
Fig. 3
Incidence of Triple X syndrome, Klinefelter syndrome and Double Y syndrome. Incidence of a Triple X syndrome; b Klinefelter syndrome; and c Double Y syndrome per million females or males during 1970–2014. Solid lines illustrate time trend in incidence during the 1970–2014. P-values indicate the significance level of time trend in incidence
Fig. 4
Fig. 4
Prevalence of sex chromosome abnormalities among newborns. a Prevalence of Turner syndrome (TS). Black bars indicates the prevalence of 45,X TS among all TS; b Triple X syndrome (Triple X); c Klinefelter syndrome (KS); and d Double Y syndrome (Double Y) during 1901–2014. Dashed lines indicate the expected prevalence and dotted lines indicate the observed maximum average prevalence of TS, Triple X, KS and Double Y per 100,000 newborn females or males
Fig. 5
Fig. 5
Age at diagnosis among sex chromosome abnormalities. Violin plots of age at diagnosis among a Klinefelter syndrome (KS), Triple X syndrome (Triple X) and Double Y syndrome (Double Y) and among b all Turner syndrome (TS), TS with a 45,X karyotype and TS with other karyotypes, diagnosed during 1970–2014. The small circle in the middle of the plot is median age, the dark rectangle depicts interquartile range, the thin dark lines depicts 95% confidence interval, and the density plot width equals frequency of age at diagnosis

References

    1. Linden MG, Bender BG, Robinson A. Sex chromosome tetrasomy and pentasomy. Pediatrics. 1995;96:672–682.
    1. Bojesen A, Juul S, Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab. 2003;88:622–626. doi: 10.1210/jc.2002-021491.
    1. Stochholm K, Juul S, Juel K, Naeraa RW, Gravholt CH. Prevalence, incidence, diagnostic delay, and mortality in turner syndrome. J Clin Endocrinol Metab. 2006;91:3897–3902. doi: 10.1210/jc.2006-0558.
    1. Kirstine S, Svend J, Højbjerg GC. Mortality and incidence in women with 47,XXX and variants. Am J Med Genet A. 2010;152A:367–372. doi: 10.1002/ajmg.a.33214.
    1. Stochholm K, Juul S, Gravholt CH. Diagnosis and mortality in 47,XYY persons: a registry study. Orphanet J Rare Dis. 2010;5:15. doi: 10.1186/1750-1172-5-15.
    1. Bochkov NP, Kuleshov NP, Chebotarev AN, Alekhin VI, Midian SA. Population cytogenetic investigation of newborns in Moscow. Hum Genet. 1974;22:139–152.
    1. Hamerton JL, Canning N, Ray M, Smith S. A cytogenetic survey of 14,069 newborn infants. I. Incidence of chromosome abnormalities. Clin Genet. 1975;8:223–243. doi: 10.1111/j.1399-0004.1975.tb01498.x.
    1. Imaizumi KKY. Prevalence of turner syndrome in Japan. In: Hibi I, Takano K, editors. Basic and clinical approach to turner syndrome. Amsterdam: Excerpta Medica; 1993. pp. 3–6.
    1. Jacobs PA, Melville M, Ratcliffe S, Keay AJ, Syme J. A cytogenetic survey of 11,680 newborn infants. Ann Hum Genet. 1974;37:359–376. doi: 10.1111/j.1469-1809.1974.tb01843.x.
    1. Nielsen J, Wohlert M. Sex chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Birth Defects Orig Artic Ser. 1990;26:209–223.
    1. Higurashi M, Iijima K, Ishikawa N, Hoshina H, Watanabe N. Incidence of major chromosome aberrations in 12,319 newborn infants in Tokyo. Hum Genet. 1979;46:163–172. doi: 10.1007/BF00291918.
    1. Ratcliffe SH. Development of children with sex chromosome abnormalities. Proc R Soc Med. 1976;69:189–191.
    1. Taylor AI, Moores EC. A sex chromatin survey of newborn children in two London hospitals. J Med Genet. 1967;4:258–259. doi: 10.1136/jmg.4.4.258.
    1. Goad WB, Robinson A, Puck TT. Incidence of aneuploidy in a human population. Am J Hum Genet. 1976;28:62–68.
    1. Maeda T, Ohno M, Matsunobu A, Yoshihara K, Yabe N. A cytogenetic survey of 14,835 consecutive liveborns. Jinrui Idengaku Zasshi. 1991;36:117–129. doi: 10.1007/BF01876812.
    1. Elsheikh M, Dunger DB, Conway GS, Wass JA. Turner’s syndrome in adulthood. Endocr Rev. 2002;23:120–140.
    1. Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E. Klinefelter’s syndrome. Lancet. 2004;364:273–283. doi: 10.1016/S0140-6736(04)16678-6.
    1. Bojesen A, Gravholt CH. Morbidity and mortality in Klinefelter syndrome (47,XXY) Acta Paediatr. 2011;100:807–813. doi: 10.1111/j.1651-2227.2011.02274.x.
    1. Swerdlow AJ, Schoemaker MJ, Higgins CD, Wright AF, Jacobs PA. Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst. 2005;97:1204–1210. doi: 10.1093/jnci/dji240.
    1. Gravholt CH, Juul S, Naeraa RW, Hansen J. Morbidity in turner syndrome. J Clin Epidemiol. 1998;51:147–158. doi: 10.1016/S0895-4356(97)00237-0.
    1. Bojesen A, Stochholm K, Juul S, Gravholt CH. Socioeconomic trajectories affect mortality in Klinefelter syndrome. J Clin Endocrinol Metab. 2011;96:2098–2104. doi: 10.1210/jc.2011-0367.
    1. Stochholm K, Hjerrild B, Mortensen KH, Juul S, Frydenberg M, Gravholt CH. Socioeconomic parameters and mortality in turner syndrome. Eur J Endocrinol. 2012;166:1013–1019. doi: 10.1530/EJE-11-1066.
    1. Stochholm K, Juul S, Gravholt CH. Socio-economic factors affect mortality in 47,XYY syndrome-a comparison with the background population and Klinefelter syndrome. Am J Med Genet A. 2012;158a:2421–2429. doi: 10.1002/ajmg.a.35539.
    1. Stochholm K, Juul S, Gravholt CH. Poor socio-economic status in 47,XXX --an unexpected effect of an extra X chromosome. Eur J Med Genet. 2013;56:286–291. doi: 10.1016/j.ejmg.2013.03.008.
    1. Sävendahl L, Davenport ML. Delayed diagnoses of Turner’s syndrome: proposed guidelines for change. J Pediatr. 2000;137:455–459. doi: 10.1067/mpd.2000.107390.
    1. Herlihy AS, Gillam L, Halliday JL, McLachlan RI. Postnatal screening for Klinefelter syndrome: is there a rationale? Acta Paediatr. 2011;100:923–933. doi: 10.1111/j.1651-2227.2011.02151.x.
    1. Lee MC, Conway GS. Turner's syndrome: challenges of late diagnosis. Lancet Diabetes Endocrinol. 2014;2:333–338. doi: 10.1016/S2213-8587(13)70153-0.
    1. Gravholt CH, Andersen NH, Conway GS, Dekkers OM, Geffner ME, Klein KO, et al. Clinical practice guidelines for the care of girls and women with turner syndrome: proceedings from the 2016 Cincinnati international turner syndrome meeting. Eur J Endocrinol. 2017;177:G1–g70. doi: 10.1530/EJE-17-0430.
    1. Gravholt CH, Chang S, Wallentin M, Fedder J, Moore P, Skakkebaek A. Klinefelter syndrome - integrating genetics, neuropsychology and endocrinology. Endocr Rev. 2018;39(4):389–423. doi: 10.1210/er.2017-00212.
    1. Schmidt M, Schmidt SA, Sandegaard JL, Ehrenstein V, Pedersen L, Sorensen HT. The Danish National Patient Registry: a review of content, data quality, and research potential. Clin Epidemiol. 2015;7:449–490. doi: 10.2147/CLEP.S91125.
    1. Helweg-Larsen K. The Danish register of causes of death. Scand J Public Health. 2011;39:26–29. doi: 10.1177/1403494811399958.
    1. Groth KA, Hove H, Kyhl K, Folkestad L, Gaustadnes M, Vejlstrup N, et al. Prevalence, incidence, and age at diagnosis in Marfan syndrome. Orphanet J Rare Dis. 2015;10:153. doi: 10.1186/s13023-015-0369-8.
    1. Jeon KC, Chen LS, Goodson P. Decision to abort after a prenatal diagnosis of sex chromosome abnormality: a systematic review of the literature. Genet Med. 2012;14:27–38. doi: 10.1038/gim.0b013e31822e57a7.
    1. Viuff MH, Stochholm K, Uldbjerg N, Nielsen BB, Gravholt CH. Only a minority of sex chromosome abnormalities are detected by a national prenatal screening program for Down syndrome. Hum Reprod. 2015;30:2419–2426. doi: 10.1093/humrep/dev192.
    1. Petersen OB, Vogel I, Ekelund C, Hyett J, Tabor A. Potential diagnostic consequences of applying non-invasive prenatal testing: population-based study from a country with existing first-trimester screening. Ultrasound Obstet Gynecol. 2014;43:265–271. doi: 10.1002/uog.13270.
    1. Tuke MA, Ruth KS, Wood AR, Beaumont RN, Tyrrell J, Jones SE, et al. Mosaic turner syndrome shows reduced penetrance in an adult population study. Genet Med. 2018 [Epub ahead of print].
    1. El-Mansoury M, Barrenas ML, Bryman I, Hanson C, Larsson C, Wilhelmsen L, et al. Chromosomal mosaicism mitigates stigmata and cardiovascular risk factors in turner syndrome. Clin Endocrinol. 2007;66:744–751. doi: 10.1111/j.1365-2265.2007.02807.x.
    1. Aksglaede L, Garn ID, Hollegaard MV, Hougaard DM, Rajpert-De Meyts E, Juul A. Detection of increased gene copy number in DNA from dried blood spot samples allows efficient screening for Klinefelter syndrome. Acta Paediatr. 2012;101:e561–e563. doi: 10.1111/apa.12008.
    1. Bojesen A, Juul S, Birkebaek NH, Gravholt CH. Morbidity in Klinefelter syndrome: a Danish register study based on hospital discharge diagnoses. J Clin Endocrinol Metab. 2006;91:1254–1260. doi: 10.1210/jc.2005-0697.
    1. Bardsley MZ, Kowal K, Levy C, Gosek A, Ayari N, Tartaglia N, et al. 47,XYY syndrome: clinical phenotype and timing of ascertainment. J Pediatr. 2013;163:1085–1094. doi: 10.1016/j.jpeds.2013.05.037.
    1. Otter M, Schrander-Stumpel CTRM, Curfs LMG. Triple X syndrome: a review of the literature. Eur J Hum Genet. 2010;18:265–271. doi: 10.1038/ejhg.2009.109.
    1. Skakkebaek A, Gravholt CH, Rasmussen PM, Bojesen A, Jensen JS, Fedder J, et al. Neuroanatomical correlates of Klinefelter syndrome studied in relation to the neuropsychological profile. Neuroimage Clin. 2014;4:1–9. doi: 10.1016/j.nicl.2013.10.013.
    1. Tartaglia NR, Howell S, Sutherland A, Wilson R, Wilson L. A review of trisomy X (47,XXX) Orphanet J Rare Dis. 2010;5:8. doi: 10.1186/1750-1172-5-8.
    1. Collaer ML, Geffner ME, Kaufman FR, Buckingham B, Hines M. Cognitive and behavioral characteristics of turner syndrome: exploring a role for ovarian hormones in female sexual differentiation. Horm Behav. 2002;41:139–155. doi: 10.1006/hbeh.2001.1751.
    1. Bishop DV, Jacobs PA, Lachlan K, Wellesley D, Barnicoat A, Boyd PA, et al. Autism, language and communication in children with sex chromosome trisomies. Arch Dis Child. 2011;96:954–959. doi: 10.1136/adc.2009.179747.
    1. Grosse SD, Rogowski WH, Ross LF, Cornel MC, Dondorp WJ, Khoury MJ. Population screening for genetic disorders in the 21st century: evidence, economics, and ethics. Public Health Genomics. 2010;13:106–115. doi: 10.1159/000226594.
    1. Barr ML, Sergovich FR, Carr DH, Saver EL. The triplo-X female: an appraisal based on a study of 12 cases and a review of the literature. Can Med Assoc J. 1969;101:247–258.
    1. Davenport ML. Approach to the patient with turner syndrome. J Clin Endocrinol Metab. 2010;95:1487–1495. doi: 10.1210/jc.2009-0926.

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